Ponatinibum

Uses

Ponatinibum is a kinase inhibitor used for the:

• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is used.
• Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Ponatinibum is also used to associated treatment for these conditions: Accelerated phase chronic myologenic leukemia, Acute Lymphoblastic Leukaemias (ALL), Chronic Phase Chronic Myeloid Leukemia, Blast phase Chronic myelocytic leukemia

How Ponatinibum works

Ponatinibum is a multi-target kinase inhibitor. Its primary cellular target is the Bcr-Abl tyrosine kinase protein which is constitutively active and promotes the progression of CML. This protein arises from the fused Bcr and Abl gene- what is commonly known as the Philadelphia chromosome. Ponatinibum is unique in that it is especially useful in the treatment of resistant CML because it inhibits the tyrosine kinase activity of Abl and T315I mutant kinases. The T315I mutation confers resistance in cells as it prevents other Bcr-Abl inhibitors from binding to the Abl kinase. Other targets that ponatinib inhibits are members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. A decrease in tumour size expressing native or T315I mutant BCR-ABL have been observed in rats.

Dosage

Ponatinibum dosage

Recommended dose: 45 mg taken orally once daily with or without food

Hepatic Impairment: 30 mg orally once daily. Modify or interrupt dosing for hematologic and non-hematologic toxicity

Side Effects

The most common non-hematologic adverse reactions (≥20%) were, abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity.

Toxicity

The most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Food Interaction

• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of ponatinib and may reduce its serum concentration.
• Exercise caution with grapefruit products. If coadministration of ponatinib and grapefruit is necessary, reduce the dose of ponatinib.
• Take with or without food.

[Moderate] GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of ponatinib, which is primarily metabolized by CYP450 3A4.

However, the interaction has not been studied.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided during treatment with ponatinib.

Ponatinibum Drug Interaction

Major: aluminum hydroxide / aspirin / calcium carbonate / magnesium hydroxideModerate: lactobacillus acidophilus, fexofenadine, morphine, nilotinibMinor: famotidineUnknown: charcoal, amphetamine / dextroamphetamine, diphenhydramine, tadalafil, ubiquinone, omega-3 polyunsaturated fatty acids, metoprolol, metoprolol, amlodipine, acetaminophen, metoprolol, cyanocobalamin, pyridoxine, cholecalciferol

Ponatinibum Disease Interaction

Major: liver impairmentModerate: cardiovascular disease, fluid retention, bone marrow suppression, lung toxicity

Volume of Distribution

After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the steady state volume of distribution is 1223 L. Ponatinibum is a weak substrate for P-gp and ABCG2.

Elimination Route

The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within 6 hours after Iclusig oral administration. Food does not affect absorption of food. The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. When 45 mg of ponatinib is given to cancer patients, the pharmacokinetic parameters are as follows: Cmax = 73 ng/mL; AUC = 1253 ng•hr/mL;

Half Life

After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the terminal elimination half-life is 24 hours (range of 12 - 66 hours).

Elimination Route

Ponatinibum is mainly eliminated via feces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.

Pregnancy & Breastfeeding use

Based on its mechanism of action and findings in animals, Ponatinibum can cause fetal harm when administered to a pregnant woman. There are no available data on Ponatinibum use in pregnant women. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to a fetus.

There is no data on the presence of ponatinib in human milk, the effects on the breastfed infant or on milk production.

Contraindication

None

Storage Condition

Store Ponatinibum at room temperature between 20° C to 25° C

Innovators Monograph

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